chr7-73669468-C-T

Variant names:

• chr7-73669468-C-T
• rs370705512
• NM_001077621.2:c.188C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001077621.2(VPS37D):​c.188C>T​(p.Ala63Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,580,478 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: VPS37D NM_001077621.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.777
• Publications: 0 publications found

Genes affected

VPS37D (HGNC:18287): (VPS37D subunit of ESCRT-I) Predicted to be involved in protein targeting to membrane; protein targeting to vacuole; and ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway. Located in extracellular exosome. Part of ESCRT I complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.088446796).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077621.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS37D	NM_001077621.2	MANE Select	c.188C>T	p.Ala63Val	missense	Exon 2 of 4	NP_001071089.1	Q86XT2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS37D	ENST00000324941.5	TSL:1 MANE Select	c.188C>T	p.Ala63Val	missense	Exon 2 of 4	ENSP00000320416.4	Q86XT2
	VPS37D	ENST00000965880.1		c.188C>T	p.Ala63Val	missense	Exon 2 of 4	ENSP00000635939.1
	VPS37D	ENST00000903466.1		c.188C>T	p.Ala63Val	missense	Exon 2 of 4	ENSP00000573525.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152240 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000576 AC: 11 AN: 191072 AF XY: 0.0000578

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000346

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000255 AC: 364 AN: 1428238 Hom.: 1 Cov.: 31 AF XY: 0.000242 AC XY: 171 AN XY: 707640

African (AFR) AF: 0.0000611 AC: 2 AN: 32734

American (AMR) AF: 0.0000250 AC: 1 AN: 39936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25496

East Asian (EAS) AF: 0.00 AC: 0 AN: 37786

South Asian (SAS) AF: 0.0000367 AC: 3 AN: 81772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5062

European-Non Finnish (NFE) AF: 0.000318 AC: 349 AN: 1095904

Other (OTH) AF: 0.000153 AC: 9 AN: 58992

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152240 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

African (AFR) AF: 0.0000241 AC: 1 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000167 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000265 AC: 1

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.0000670 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.78
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.16
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.029	D
Polyphen		0.25	B
Vest4		0.31
MVP		0.082
MPC		0.38
ClinPred		0.13	T
GERP RS		3.4
Varity_R		0.15
gMVP		0.29
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs370705512; hg19: chr7-73083798;